Thread by @DyorsMathew

/ 🧵III. Why is immunity not “binary” (immune vs not immune against a pathogen)?

This thread is part 3 of 7 of the mother thread #FreshStart2PublicDebate.

/ Our immune system has two arms: the innate immune system and the adaptive immune system. The innate immune system is the first line of defense. It sends out the alarm that something is wrong. It generally recognizes patterns in cells that help sort self from pathogens.

/ For example, when an innate immune cell comes into contact with a bacteria cell, it identifies it as not self because bacteria have a cell wall structure that’s not found in human cells.

/ The adaptive immune system includes the T cells and B cells. Unlike the cells of the innate immune system, T cells and B cells can identify specific features of pathogens. Adaptive immunity recognizes changes in the proteins cells produce and identifies the cell as harmful.

/ B cells create antibodies. B lymphocytes, also called B cells, create a type of protein called an antibody. These antibodies bind to pathogens or to foreign substances, such as toxins, to neutralize them.

/ For example, an antibody can bind to a virus, which prevents it from entering a normal cell and causing infection. B cells can also recruit other cells to help destroy an infected cell.

/ Lymphocytes are a type of white blood cells. Cellular immunity is based on T cells. Without T lymphocytes, also called T cells, every exposure to a pathogen could be life-threatening. They also direct the immune response by helping B lymphocytes to eliminate invading pathogens.

/ T cells originate in bone marrow and then mature in the thymus, perform multiple different roles as the human body matures and ages. Some T cells, for example, regulate the immune response while others directly bind to and kill cells infected by cancer or viruses.

/ Others survey the body for signs of cancer. And some are simply “naive”: young cells not yet stimulated by an antigen.

/ CD4+ are helper T cells that help the activity of other immune cells by releasing cytokines. The cytokines prime the maturation of B cells, which become plasma cells and produce antibodies to neutralize a pathogen. CD8+ cytotoxic T cells directly kill infected cells.

/ Memory T cells can remember a foreign invader and lead the charge against reinfection. T cells can also secrete chemicals that help B cells produce antibodies. As a general rule T cells protect against reinfection by providing durable memory of past invaders.

/ Once the adaptive immune system has vanquished the invader, a pool of long-lived memory T and B cells are made. These memory lymphocytes remain dormant until the next time they encounter the same pathogen.

/ This time, though, they produce a much faster and stronger immune reaction. Memory is the key feature of the adaptive immune system, enabling long-term protection.

/ B cells and T cells specialized to fight a pathogen wane over time. What remains are memory cells. An infection with #SARSCoV2 will, hence, temporarily provide immunity against reinfection from the same variant.

/ This immunity wanes, as discussed in the following publication:
academic.oup.com/jtm/advance-ar…

/ The protection will be weaker (it is referred to as cross-immunity) and wanes faster against another variant. The more different the variant is (i.e., the more antigenic drift with respect to the variant with which the infection took place), the faster the waning.

/ Thus, unfortunately, “immunity” is a sometimes misunderstood to be binary (immune vs. not immune). Immunity in the sense of protection against infection has to be distinguished from protection against severe disease and also from immunity against #LongCovid.

/ Moreover, immunity wanes. This is in the nature of the human body. One might even argue that this has something to do with the second law of thermodynamics.

/ What is essential, is that certain antibodies procued by B cells protect very well against severe disease and death. Put differently, these antibodies are a good correlate of protection against severe disease and death. However, the antibodies and B cells disappear.

/ As of November 2022, there is no data available that would suggest that memory cells or, e.g., any type of T cells are a good correlate protection against severe disease and death.

/ Thus, regular vaccination or timely reinfection would appear to be the only way to remain reasonably protected.

/ As of November 2022, there is also no data available that would suggest that memory cells or, more generally, any type of memory B cells or T cells are a good correlate protection against #LongCovid.

/ A good correlate of protection against #LongCovid is not to get infected. At present, this means that preventing #LongCovid is mainly avoided by avoiding exposure to #SARSCov2.

/ If there were oral vaccines that induce strong immunity in the epithelium, then one would hopefully be able to prevent infection despite exposure.

/ That #SARSCov2 is not a suitable virus to co-exist with humans after a matter of months or years, is not surprising. #SARSCoV2 is essentially a bat virus, wherein bats and this virus co-evolved to symbiotically co-exist.

/ Symbioses between hosts and viruses are well known.
pubmed.ncbi.nlm.nih.gov/28787582/

/ Coronaviruses may be considered “protector” viruses that symbiotically co-exist with bats to protect bats from an invasion of their habitat.

https://twitter.com/DyorsMathew/status/1457741183610933253?s=20

/ Bats’ immune defenses may be why their viruses can be so deadly to people

https://twitter.com/ScienceNews/status/1230348854983380994?s=20&t=PJpgW0JQZ7scGHOV5S09JQ

/ What is special to the immune system to bats and why one may find cues to LongCovid.

https://twitter.com/DyorsMathew/status/1575038710898659329?s=20&t=PJpgW0JQZ7scGHOV5S09JQ

/ #SARSCoV2 has similarities with other bat-origin viruses: SARS-CoV-1 or MERS. nature.com/articles/nrmic…

/ Moreover, #SARSCoV2 rapidly mutates/evolves. Antigenic drift describes the phenomenon of the virus changing, in order to evade pre-existing immunity.

/ The global rate of change is so high that people would need to expect to get reinfected by #SARSCoV2 more than once, and probably several times per year without mitigating measures preventing infections.

/ #SARSCov2 is constantly evolving, i.e., it undergoes mutation and selection. Put simply, if a person is infected and the virus mutates, what will be selected is what replicates faster. Faster replicating variants that generate hgher viral loads will infect more efficiently.

/ There is, hence, positive selective pressure on more transmissible variants. However, there is also a counterforce at work: the existing immunity in the population. Thus, how well a variant transmits always depends on the background immunity of the population.

/ The intrinsic replication number R0 is thus at every point in time t modified by virtue of existing immunity and, if present, by non pharmaceutical interventions and thus to be replaced by R(t).

/ R(t) depends on the immunity, or, to be more precise, on the existin B memory cells, T memory cells, B cells, and T cells, etc. R(t)=R(t; R(IGAAbs, IgGAbs, IgMAbs, Bcell,Tcell, Bimcell, Tmemcell, etc.).

/ When a variant (or a chain of similar variants) has hit a fitness maximum within a biological subspace and/or when existing immuntiy in the population becomes an obstacle, the antigentic drift becomes more important.

/ Immune evasion becomes more and more important. There is positive selective pressure on faster replication, but also on immune evasion, and these two factors are in a balance depending on the background immunity.

/ The number of infections worldwide equals the number of hosts and thus stands in a direct relationship to the number of possibilities for the virus to mutate and to produce a new immune evasive and fast replicating variant.

/ The evolution speed of #SARSCoV2 is thus strongly determined by the worldwide number of infections. However, a special role is played by immunocompromised people and by chronic infection.

/ Chronic infection describes the longterm infection (similar to a HIV infection), wherein the host´s immune system does not clear the virus over the time. In this case, the virus is constantly exposed to immune pressure and thus evolves rapidly within the host.

/ Evolutionary jumps to produce new variants of concern have in the meantime repeatedly been linked to intrahost accelerated evolution. Therefore, protecting vulnerable people also protects the world from immune evasive and thus dangerous variants.

/ The strong affinity towards chronic infection by #SARSCoV2 is a major different with respect to the currently circulating human Influenza strains.

/ In the first 18 months of spreading #SARSCoV2, about 2.9 amino acid exchanges per year in the spike protein appeared for basic variants For "variants of concern", based on evolutionary leaps (presumably, due to chronic infections), there were approx. 8-10 am.acid exchanges p.a.

/ For comparison: the fastest evolving influenza H3N2 has about 2.5 amino acid exchanges per year in the haemagglutinin (the H-surface protein of influenza). In H1N1 there are about 1.5 amino acid exchanges per year.

/ Link to the mother thread

https://twitter.com/DyorsMathew/status/1590427508226551808?s=20&t=3FW47lwoIyVM2dQKm9T1jw